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Prevention and treatment of androgen-deprivation induced osteoporosis

a technology of androgen deprivation and osteoporosis, which is applied in the field of prevention and treatment of androgen deprivation induced osteoporosis, can solve the problems of osteoporosis, androgen deprivation therapy is fraught with significant side effects, and achieves the effect of safe and effective treatmen

Inactive Publication Date: 2009-04-28
GTX INCORPORATED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]This invention relates to a method of reducing the risk of developing androgen-deprivation induced osteoporosis in a male subject suffering from prostate cancer, the method comprising the step of administering to said subject an anti-estrogen agent and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof.
[0015]This invention relates to a method of reducing the risk of developing androgen-deprivation induced loss of BMD in a male subject suffering from prostate cancer, the method comprising the step of administering to said subject an anti-estrogen agent and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof.
[0019]This invention relates to a method of reducing the risk of developing androgen-deprivation induced bone fractures in a male subject suffering from prostate cancer, the method comprising the step of administering to said subject an anti-estrogen agent and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof.
[0023]The present invention provides a safe and effective method for treating, preventing, suppressing, inhibiting or reducing the risk of developing androgen-deprivation induced osteoporosis and / or loss of BMD and is particularly useful for treating male subjects suffering from prostate cancer having an elevated risk of developing androgen-deprivation induced osteoporosis and / or loss of BMD.

Problems solved by technology

Consequently, when androgen or estrogen deprivation occurs, there is a resultant increase in the rate of bone remodeling that tilts the balance of resorption and formation in the favor of resorption, contributing to an overall loss of bone mass.
Unfortunately, androgen deprivation therapy is fraught with significant side effects, including hot flashes, gynecomastia, osteoporosis, decreased lean muscle mass, depression and other mood changes, loss of libido, and erectile dysfunction [Stege R (2000), Prostate Suppl 10,38-42].
Consequently, complications of androgen blockade now contribute significantly to the morbidity, and in some cases the mortality, of men suffering from prostate cancer.

Method used

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  • Prevention and treatment of androgen-deprivation induced osteoporosis
  • Prevention and treatment of androgen-deprivation induced osteoporosis
  • Prevention and treatment of androgen-deprivation induced osteoporosis

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effect of Toremifene on Bone Turnover in Human Male Subjects

[0094]In a Phase IIa clinical trial to determine whether Toremifene has chemopreventive activity against prostate cancer, 18 men with high-grade prostatic intraepithelial neoplasia (HGPIN) were treated with 60 mg / d of Toremifene for 4 months. At Day 120 there was a significant reduction from baseline in serum calcium (mean −0.12, p=0.005) and at both day 60 and day 120, alkaline phosphatase was significantly decreased compared to baseline (mean=−18.7 at Day 60 and −21.0 at Day 120, and p<0.001 for both visits).

[0095]These clinical data demonstrate that the anti-estrogen Toremifene showed estrogenic effects on bone favorably affecting bone turnover markers in men.

example 2

Effect of Toremifene on Bone in Male Rats

Drug Delivery System

[0096]The test article, positive control and placebo were delivered by ALZA pumps manufactured by Durect Corporation (Cupertino, Calif.). Pumps were implanted in a subcutaneous pocket using appropriate surgical technique. The pumps employed in this study deliver a continuous rate of drug over a 30-day period with Toremifene formulated to release 1.8 mg / day (2 mL pump) and 17-β-Estradiol (positive control) released at 70 ug / day. Data provided by the manufacturer of the pumps validates the constant rate of drug delivery over a 28-day period, and suggests that the constant rate can be expected for several additional days. Animals were anesthetized and pump replacement was performed for each dosage group on days 31, 61, and 91 to provide drug administration over a 120-day period. Every animal on study had a pellet implanted to control for potential confounding variables associated with surgery for implantation.

Study Groups:

[00...

example 3

Effect of Toremifene on Bone Density and Serum Markers for Bone Remodeling in Male Rats

[0111]The purpose of this study is to determine whether administration of Toremifene to mature male rats is bone sparing as can presently be measured by the levels of bone-specific serum markers that indicate bone resorption and formation (where 17-β-Estradiol is used as a positive control). The effect of Toremifene (and 17-β-Estradiol) on androgen deprivation-induced bone loss was also determined through bone density and mechanical strength testing.

[0112]The model used herein is an orchidectomy model, which is an experimental model used to mimic the type of androgen deprivation that would be caused by, for example, LHRH agonist therapy in prostate cancer.

Materials and Methods

Study Design

[0113]Male Sprague-Dawley rats (Harlan Sprague Dawley) were placed on study at 14-weeks of age. They were randomized and divided into five treatment groups: vehicle only (placebo, or P) after sham operation, vehic...

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Abstract

This invention provides: 1) a method of treating androgen-deprivation induced osteoporosis and / or bone fractures and / or loss of Bone Mineral Density (BMD) in a male subject suffering from prostate cancer; 2) a method of preventing androgen-deprivation induced osteoporosis and / or bone fractures and / or loss of Bone Mineral Density (BMD) in a male subject suffering from prostate cancer; 3) a method of suppressing or inhibiting androgen-deprivation induced osteoporosis and / or bone fractures and / or loss of BMD in a male subject suffering from prostate cancer; and 4) a method of reducing the risk of developing androgen-deprivation induced osteoporosis and / or bone fractures and / or loss of BMD in a male subject suffering from prostate cancer, by administering to the subject a pharmaceutical composition comprising an anti-estrogen agent and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application is a continuation-in-part of U.S. patent application Ser. No. 10 / 609,684, filed Jul. 1, 2003, now abandoned, which is a continuation-in-part of U.S. patent application Ser. No. 10 / 305,363, filed Nov. 27, 2002, now U.S. Pat. No. 6,899,888, and claims priority of U.S. Provisional Patent Application Ser. No. 60 / 333,734, filed Nov. 29, 2001, all of which are hereby incorporated in their entirety by reference herein.FIELD OF INVENTION[0002]This invention relates to reducing the incidence of, inhibiting, suppressing, preventing and treating androgen-deprivation induced osteoporosis and / or bone fractures and / or loss of bone mineral density (BMD) in men suffering from prostate cancer. More particularly, this invention relates to a method of treating, preventing, suppressing, inhibiting, or reducing the risk of developing androgen-deprivation induced osteoporosis and / or bone fractures and / or loss of BMD in men suffering from prosta...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/445A61K31/135A61K31/38A61K31/138
CPCA61K31/138
Inventor STEINER, MITCHELL S.RAGHOW, SHARANVEVERKA, KAREN A.
Owner GTX INCORPORATED
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